Until recently, the ability to differentiate into multiple tissue types was traditionally a property reserved to embryonic stem cells (8-10). Recent studies have demonstrated that tissue specific stem cells, thought to have restricted differentiation potential to the tissue from which they were derived, are capable of producing cellular phenotypes of alternative tissue upon transplantation (11,12). This cellular property of stem cells has been termed “transdifferentiation” (8). A principal example of these observations comes from transplantation of bone marrow (BM) derived stem cells that have generated unexpected phenotypes in vivo that include muscle (2-4), liver (6), brain (1,13), and cells of epithelial lineage (5). These studies suggest that the existence of an active pool of stem cells can be procured from the BM compartment that are capable of either transdifferentiation or represent less restricted cells with multiple tissue differentiation potential. In the context of regenerative therapies, adult stem cells with these properties has ignited the hope of obtaining a source of stem cells with pluripotent potential (14), thereby avoiding the necessity of obtaining human embryonic stem cells for tissue/organ repair.
Bone marrow derived stem cells have been reported by many groups (40; WO 02/13760; WO 02/09650; WO 01/21766; WO 01/21767; U.S. Pat. No. 6,174,526; and US 2002/0012653). Ikehara at al. (40) relates to the reconstitution of irradiated NOD mice with bone marrow cells from BALB/c nu/nu mice to treat insulitis or diabetes. Than et al. (41) demonstrated that allogenic bone marrow transplantation could be used to treat non-insulin-dependent diabetes in mice and could promote morphological recovery of islets.
Although BM derived stem cells have demonstrated trans- or multipotent differentiation into damaged tissue, the restoration of physiological function and implied benefit to the recipients have rarely been demonstrated (6,7). Since identification of donor cells adopting alternative tissue phenotypes alone does not adequately determine the therapeutic viability of stem cell engraftment, more recent studies have associated the number of transdifferentiating donor cells observed to liver (6) or cardiac function (7). However, the low frequency of donor cell chimerism, together with an almost complete restoration of tissue function (7), illustrates an enigmatic dichotomy between stem cell contribution and physiological recovery that has yet to be resolved.